Sigma receptors were initially proposed as opioid, and later phencyclidine receptors, and were finally demonstrated to represent unique binding sites in mammalian brain and peripheral tissues that are expressed throughout the CNS and have been implicated in a variety of physiological functions and disease states. Two subtypes of receptors have been distinguished molecularly and pharmacologically. Though several effects of cocaine related to its abuse are antagonized by sigma receptor antagonists, previous studies showed that standard &#963;R antagonists had no effects on cocaine self -administration. However, later studies showed that &#963;R antagonists that also had affinity for the DAT were effective antagonists of cocaine and methamphetamine. Subsequent studies showed that these two actions were responsible for the cocaine antagonist effects of several atypical DAT inhibitors that blocked the self administration of cocaine. To assess the generality of actions at these two targets, we examined the effects of RTI-371 3&#946;-(4-methylphenyl)-2&#946;-3-(4-chlorophenyl)-isoxazol-5-yltropane, a phenyltropane cocaine analog with high affinity for the DAT but with atypical DAT actions. RTI-371 had very low affinity for sigma receptors, but had behavioral effects like those of the atypical DAT inhibitors. RTI-371 itself was not self administered, and blocked the self administration of cocaine. Additionally, RTI-371 was less effective than cocaine in stimulating locomotion, and incompletely substituted in a cocaine/saline discrimination procedure. In contrast to RTI-336, RTI-371 was not self-administered. RTI-371 was selective for the DAT among the monoamine transporters, and had low affinity for muscarinic and &#963; receptors. The relative low affinity at these sites suggests the DAT as the primary target of RTI-371 with minimal contributions from these other targets. In biochemical assays probing the outward-facing DAT conformation, both RTI-371 and RTI-336 had effects similar to cocaine, suggesting little contribution of DAT conformation to the unique pharmacology of RTI-371. DAT occupancy by RTI-371 in vivo was significantly decreased compared to that for cocaine. The slow apparent association rate may render antagonist actions at sigma receptors unnecessary for cocaine antagonist effects. This kinetic profile may allow compensatory actions that in turn dampen cocaine-like stimulation, and give RTI-371 its unique pharmacologic profile.